Burkitt lymphoma (BL), the most common pediatric lymphoproliferative disease in developing nations, is highly associated with Epstein Barr virus (EBV). These virulent tumors can be cured with chemotherapy but relapsed or resistant disease is quite common and generally fatal. We hypothesize that the presence of EBV in the endemic form of BL can be used both to monitor response to therapy and as a therapeutic target. In our first aim we propose to study EBV viral load in BL patients enrolled on a therapeutic protocol. We will determine whether EBV viral load correlates with response to therapy or conversely with relapsing or resistant disease. We will also investigate the effect of chemotherapy on viral reactivation. We further hypothesize that the antiviral agent azidothymidine (AZT) induces apoptosis in EBV+ BL through a unique, targeted mechanism: suppression of NF-kappaB and disruption of viral latency. This results in phosphorylation of AZT by viral kinases and apoptosis. Therefore, AZT is essentially an inexpensive form of gene therapy that exploits the presence of EBV. There is no effective therapy for relapsed endemic type BLs. In aim 2 we will conduct a trial of chemo/antiviral (AZT, hydrea) therapy for these patients. Commonly available chemotherapeutic agents are known to induce the EBV lytic cycle including viral thymidine kinase and thereby potentiate phosphorylation of AZT. Our group, comprised of pediatric and adult hematologists, virologists, research nurses and pathologists offers multidisciplinary expertise required for this translational study. Our collaborators, located at a unique site where viral lymphoproliferative diseases are commonly diagnosed, have excellent infrastructure in place to participate in this study. Data acquired through this project should be broadly applicable to high grade lymphomas that occur in Immune compromised individuals. These studies should lead to new, non-carcinogenic, abbreviated therapy that is applicable in developing nations for this common tumor.